m6A甲基化修饰在食管癌中的研究进展

doi:10.12114/j.issn.1007-9572.2021.01.306

摘要/Abstract

摘要： 6-甲基腺嘌呤（m6A）作为真核细胞中最丰富的表观转录组学修饰，其在肿瘤的发生发展过程中发挥着重要的作用。目前国内外对于m6A甲基化修饰如何参与到食管癌发生、发展的研究主要集中于细胞恶性增殖、迁移和侵袭等生物功能方面。关于m6A甲基化修饰调节因子在食管癌中差异表达情况的研究认为，m6A甲基化修饰调节因子有望成为食管癌潜在的预后分子标志物。本文围绕着m6A甲基化修饰的生物功能，以及m6A甲基化修饰在食管癌中的预后价值、术后治疗等方面研究进展进行综述，旨在为食管癌的预后和靶向治疗提供新思路。

关键词: 食管肿瘤, 6-甲基腺嘌呤, RNA甲基化酶类, 综述

Abstract: N6-methyladenosine （m6A），as the most abundant epitranscriptomic modification in eukaryotic cells，plays an important role in the occurrence and development of tumors. At present，domestic and foreign research on how m6A methylation modification participates in the occurrence and development of esophageal cancer mainly focuses on the biological functions of cell malignant proliferation，migration and invasion. Research on the differential expression of m6A methylation modification regulators in esophageal cancer suggests that m6A methylation modification regulators are expected to become potential prognostic molecular markers for esophageal cancer. This review focuses on the biological functions of m6A methylation modification，as well as the prognostic value of m6A methylation in esophageal cancer，postoperative treatment and other aspects of research progress，aiming to provide new ideas for the prognosis and targeted therapy of esophageal cancer.

Key words: Esophageal neoplasms, N6-methyladenosine, RNA methylases, Review

朱凌妍,沈艺,邵毅,等. m6A甲基化修饰在食管癌中的研究进展[J]. 中国全科医学, 2021, 24(32): 4150-4154. DOI: 10.12114/j.issn.1007-9572.2021.01.306.
ZHU Lingyan,SHEN Yi,SHAO Yi, et al. The Role of m6A RNA Methylation Modification in Esophageal Cancer　[J]. Chinese General Practice, 2021, 24(32): 4150-4154. DOI: 10.12114/j.issn.1007-9572.2021.01.306.

参考文献

［1］BRAY F，FERLAY J，SOERJOMATARAM I，et al. Global cancer statistics 2018：GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries ［J］. CA Cancer J Clin，2018，68（6）：394-424. DOI：10.3322/caac.21609.
［2］WEI W Q，HAO C Q，GUAN C T，et al. Esophageal histological precursor lesions and subsequent 8.5 year cancer risk in a population-based prospective study in China ［J］. Am J Gastroenterol，2020，115（7）：1036-1044. DOI：10.14309/ajg.0000000000000640.
［3］CHEN R，LIU Y，SONG G，et al. Effectiveness of one-time endoscopic screening programme in prevention of upper gastrointestinal cancer in China：a multicentre population-based cohort study ［J］. BJM，2021，70（2）：251-260. DOI：10.1136/gutjnl-2019-320200.
［4］ZENG H，CHEN W，ZHENG R，et al. Changing cancer survival in China during 2003-15：a pooled analysis of 17 population-based cancer registries ［J］. Lancet Glob Health，2018，6（5）：e555-567. DOI：10.1016/S2214-109X（18）30127-X.
［5］NAGAKI Y，MOTOYAMA S，YAMAGUCHI T，et al. m6A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis ［J］. Genes Cells，2020，25（8）：547-561. DOI：10.1111/gtc.12792.
［6］SHI H，WEI J，HE C. Where，When，and how：context-dependent functions of RNA methylation writers，readers，and erasers ［J］. Mol Cell，2019，74（4）：640-650. DOI：10.1016/j.molcel.2019.04.025.
［7］LIU J，HARADA B T，HE C. Regulation of gene expression by N（6）-methyladenosine in cancer ［J］. Trends Cell Biol，2019，29（6）：487-499. DOI：10.1016/j.tcb.2019.02.008.
［8］ZHAO W，QI X，LIU L，et al. Epigenetic regulation of m6A modifications in human cancer ［J］. Mol Ther Nucleic Acids，2020，19：405-412. DOI：10.1016/j.omtn.2019.11.022.
［9］MUTHUSAMY S. m6A mRNA methylation：a pleiotropic regulator of cancer ［J］. Gene，2020，736:144415. DOI：10.1016/j.gene.2020.144415.
［10］ZHANG Z，LUO K，ZOU Z，et al. Genetic analyses support the contribution of mRNA N（6）-methyladenosine （m6A） modification to human disease heritability ［J］. Nat Genet，2020，52（9）：939-949. DOI：10.1038/s41588-020-0644-z.
［11］HU Y，WANG S，LIU J，et al. New sights in cancer：component and function of N6-methyladenosine modification ［J］. Biomed Pharmacother，2020，122：109694. DOI：10.1016/j.biopha.2019.109694.
［12］LAN Q，LIU P Y，HAASE J，et al. The critical role of RNA m6A methylation in cancer ［J］. Cancer Res，2019，79（7）：1285-1292. DOI：10.1158/0008-5472.CAN-18-2965.
［13］LIU L，WANG Y，WU J，et al. N（6）-methyladenosine：a potential breakthrough for human cancer ［J］. Mol Ther Nucleic Acids，2020，19：804-813. DOI：10.1016/j.omtn.2019.12.013.
［14］WANG T，KONG S，TAO M，et al. The potential role of RNA N6-methyladenosine in cancer progression ［J］. Mol Cancer，2020，19（1）：88. DOI：10.1186/s12943-020-01204-7.
［15］SHIMA H，MATSUMOTO M，ISHIGAMI Y，et al. S-adenosylmethionine synthesis is regulated by selective N（6）-adenosine methylation and mRNA degradation involving METTL16 and YTHDC1 ［J］. Cell reports，2017，21（12）：3354-3363. DOI：10.1016/j.celrep.2017.11.092.
［16］JIA G，FU Y，ZHAO X，et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO ［J］. Nat Chem Biol，2011，7（12）：885-887. DOI：10.1038/nchembio.687.
［17］CHEN J，DU B. Novel positioning from obesity to cancer：FTO，an m6A RNA demethylase，regulates tumour progression ［J］. J Cancer Res Clin Oncol，2019，145（1）：19-29. DOI：10.1007/s00432-018-2796-0.
［18］LIU S，HUANG M，CHEN Z，et al. FTO promotes cell proliferation and migration in esophageal squamous cell carcinoma through up-regulation of MMP13 ［J］. Exp Cell Res，2020，389（1）：111894. DOI：10.1016/j.yexcr.2020.111894.
［19］MAITY A，DAS B. N6-methyladenosine modification in mRNA：machinery，function and implications for health and diseases ［J］. FEBS J，2016，283（9）：1607-1630. DOI：10.1111/febs.13614.
［20］SHEN C，SHENG Y，ZHU A C，et al. RNA demethylase ALKBH5 selectively promotes tumorigenesis and cancer stem cell self-renewal in acute myeloid leukemia ［J］. Cell Stem Cell，2020，27（1）：64-80. DOI：10.1016/j.stem.2020.04.009.
［21］UEDA Y，OOSHIO I，FUSAMAE Y，et al. AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells ［J］. Sci Rep，2017，7：42271. DOI：10.1038/srep42271.
［22］LIVNEH I，MOSHITCH-MOSHKOVITZ S，AMARIGLIO N，et al. The m6A epitranscriptome：transcriptome plasticity in brain development and function ［J］. Nat Rev Neurosci，2020，21（1）：36-51. DOI：10.1038/s41583-019-0244-z.
［23］SUN T，WU R，MING L. The role of m6A RNA methylation in cancer ［J］. Biomed Pharmacother，2019，112：108613. DOI：10.1016/j.biopha.2019.108613.
［24］WANG X，LU Z，GOMEZ A，et al. N6-methyladenosine-dependent regulation of messenger RNA stability ［J］. Nature，2014，505（7481）：117-120. DOI：10.1038/nature12730.
［25］ALARCóN C R，GOODARZI H，LEE H，et al. HNRNPA2B1 is a mediator of m6A dependent nuclear RNA processing events［J］. Cell，2015，162（6）：1299-1308. DOI：10.1016/j.cell.2015.08.011.
［26］HUANG H，WENG H，SUN W，et al. Recognition of RNA N（6）-methyladenosine by IGF2BP proteins enhances mRNA stability and translation ［J］. Nat Cell Biol，2018，20（3）：285-295. DOI：10.1038/s41556-018-0045-z.
［27］NACHTERGAELE S，HE C. Chemical modifications in the life of an mRNA transcript ［J］. Annu Rev Genet，2018，52：349-372. DOI：10.1146/annurev-genet-120417-031522.
［28］ZACCARA S，RIES R J，JAFFREY S R. Reading，writing and erasing mRNA methylation ［J］. Nat Rev Mol Cell Biol，2019，20（10）：608-624. DOI：10.1038/s41580-019-0168-5.
［29］YANG N，YING P，TIAN J，et al. Genetic variants in m6A modification genes are associated with esophageal squamous-cell carcinoma in the Chinese population ［J］. Carcinogenesis，2020，41（6）：761-768. DOI：10.1093/carcin/bgaa012.
［30］HOU H，ZHAO H，YU X，et al. METTL3 promotes the proliferation and invasion of esophageal cancer cells partly through AKT signaling pathway ［J］. Pathol Res Pract，2020，216（9）：153087. DOI：10.1016/j.prp.2020.153087.
［31］HU W，LIU W，LIANG H，et al. Silencing of methyltransferase-like 3 inhibits oesophageal squamous cell carcinoma ［J］. Exp Ther Med，2020，20（6）：138. DOI：10.3892/etm.2020.9267.
［32］XUE J，XIAO P，YU X，et al. A positive feedback loop between AlkB homolog 5 and miR-193a-3p promotes growth and metastasis in esophageal squamous cell carcinoma ［J］. Hum Cell，2020. DOI：10.1007/s13577-020-00458-z.
［33］ZHANG Y，CHEN W，PAN T，et al. LBX2-AS1 is activated by ZEB1 and promotes the development of esophageal squamous cell carcinoma by interacting with HNRNPC to enhance the stability of ZEB1 and ZEB2 mRNAs ［J］. Biochem Biophys Res Commun，2019，511（3）：566-572. DOI：10.1016/j.bbrc.2019.02.079.
［34］GUO H，WANG B，XU K，et al. m6A reader HNRNPA2B1 promotes esophageal cancer progression via up-regulation of ACLY and ACC1 ［J］. Front Oncol，2020，10：553045. DOI：10.3389/fonc.2020.553045.
［35］QU Y，PAN S，KANG M，et al. MicroRNA-150 functions as a tumor suppressor in osteosarcoma by targeting IGF2BP1 ［J］. Tumour Biol，2016，37（4）：5275-5284. DOI：10.1007/s13277-015-4389-8.
［36］YAN A，WANG C，ZHENG L，et al. MicroRNA-454-3p inhibits cell proliferation and invasion in esophageal cancer by targeting insulin-like growth factor 2 mRNA-binding protein 1 ［J］. Oncol Lett，2020，20（6）：359. DOI：10.3892/ol.2020.12223.
［37］TANG W，CHEN S，LIU J，et al. Investigation of IGF1，IGF2BP2，and IGFBP3 variants with lymph node status and esophagogastric junction adenocarcinoma risk ［J］. J Cell Biochem，2019，120（4）：5510-5518. DOI：10.1002/jcb.27834.
［38］XU X，SONG C，CHEN Z，et al. Downregulation of HuR inhibits the progression of esophageal cancer through interleukin-18 ［J］. Cancer Res Treat，2018，50（1）：71-87. DOI：10.4143/crt.2017.013.
［39］LI H，ZHANG C，ZHANG M，et al. Angustoline inhibited esophageal tumors through regulating LKB1/AMPK/ELAVL1/LPACT2 pathway and phospholipid remodeling ［J］. Front Oncol，2020，10：1094. DOI：10.3389/fonc.2020.01094.
［40］ZHOU Z，LYU J，YU H，et al. Mechanism of RNA modification N6-methyladenosine in human cancer ［J］. Mol Cancer，2020，19（1）：104. DOI：10.1186/s12943-020-01216-3.
［41］XU L C，PAN J X，PAN H D. Construction and validation of an m6A RNA methylation regulators-based prognostic signature for esophageal cancer ［J］. Cancer Manag Res，2020，12:5385-5394. DOI：10.2147/CMAR.S254870.
［42］XIA T L，YAN S M，YUAN L，et al. Upregulation of METTL3 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma ［J］. Cancer Manag Res，2020，12：5729-5737. DOI：10.2147/CMAR.S245019.
［43］WAKITA A，MOTOYAMA S，SATO Y，et al. IGF2BP3 expression correlates with poor prognosis in esophageal squamous cell carcinoma ［J］. J Surg Res，2020，259:137-144. DOI：10.1016/j.jss.2020.10.024.
［44］LIU T，LI R，ZHAO H，et al. eIF4E promotes tumorigenesis and modulates chemosensitivity to cisplatin in esophageal squamous cell carcinoma ［J］. Oncotarget，2016，7（41）：66851-66864. DOI：10.18632/oncotarget.11694.
［45］LIU X S，YUAN L L，GAO Y，et al. Overexpression of METTL3 associated with the metabolic status on 18F-FDG PET/CT in patients with esophageal carcinoma ［J］. J Cancer，2020，11（16）：4851-4860. DOI：10.7150/jca.44754.

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